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This presentation will discuss unapproved or investigational use of various probiotic preparations. Professor Tarnow-Mordi has no commercial or financial relationship relating to this presentation.

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The many researchers, clinicians and families who have contributed to RCTs or systematic reviews of probiotics in preterm infants deserve great credit. Their work is sincerely acknowledged.

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Outline Three current priorities Evidence based medicine and patient preference Parallels with antibiotics for colorectal surgery Rationale for more placebo RCTs What should parents be told? Can we reach a consensus for global collaboration?

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Three current priorities

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 Continue research on probiotics  Disclose to parents and Institutional Review Boards current evidence that probiotics halve mortality rates  Assess whether probiotics can be made more widely accessible in RCTs and cohort studies

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Evidence based medicine and patient preference

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Evidence based medicine Sackett et al, BMJ 1996: 312: decision making is based on three fundamentals:- patients' circumstances best research evidence patients' preferences

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Howard Bauchner, 2010 Editor: Journal Watch Pediatrics and Adolescent Medicine “ My suggestion is to discuss with parents the benefits, as well as arguments against routine probiotic use, and let them decide.” May 26, 2010

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Edmund Hey (1934 – 2009) Editor: Neonatal Formulary 5 “Do we, knowing what we now know, have the right to deny parents the option of giving a probiotic...?” Hey, E. Comment: Neonatal Formulary 5 Has the time come to start using probiotics more widely? edicine/bmj/nnf5/pdfs/comment/pro b_com_jul09.pdf

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Who is setting the agenda? Parents’ preferences and options have received little attention so far.

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The James Lind Alliance … to bring patients and clinicians together in 'Priority Setting Partnerships' to identify and prioritise the unanswered questions that they agree are most important.

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A key question After each death without access to open label probiotic - particularly deaths from NEC - will clinicians, IRBs, managers and parents be satisfied that sufficient information and choices were given?

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Parallels with antibiotics for colorectal surgery

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Sir Iain Chalmers, 2007 Editor: James Lind Library “Would any of you have agreed to participate in a placebo controlled trial of prophylactic antibiotics for colorectal surgery after 1975?”

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In the next 12 years, 11 more RCTs reported another 928 patients, with little change in the odds of death. Half - over received no antibiotics. On balance of probability, most deaths in these patients could be ascribed to that omission.

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Antibiotic prophylaxis for colorectal surgery Lau et al: J Clin Epidemiol 1995 “ Withholding all antibiotics from control group patients is hardly justifiable if it is known from pooling of all antibiotic trials that … lives are saved.”

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Two important differences Antibiotics were routinely available for adults undergoing colorectal surgery and clinicians were experienced in using them. Previously evaluated, locally approved probiotics are not yet routinely accessible for preterm infants in most jurisdictions.

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As probiotics become more widely available, parallels with antibiotic prophylaxis in colorectal surgery will become closer.

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5. Better estimates of risk - ? Potential risks of probiotics, such as sepsis, allergy, antibiotic resistance are important. But these must be balanced against current evidence showing a substantial increase in mortality in controls. Large cohort/ Phase IV studies may estimate risks more reliably than RCTs

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6. The current meta analysis suffers from heterogeneity - X There is no evidence of heterogeneity. Relative risks for mortality in all RCTs are < 1.0 and confidence intervals overlap. I 2 = 0.

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7. Access to probiotics may help clinicians gain experience and confidence - √ But only half the infants will get probiotics in RCTs. Special access schemes or non randomised prospective cohort or case-control studies could allow the option of access for all eligible infants.

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8. Many clinicians remain substantially uncertain about the evidence - √ If so, a RCT is an appropriate option for those clinicians. However, clinicians may also wish –to ensure access to probiotics for eligible infants –discuss the options with parents and let them decide.

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Information should be given in as much detail as for a placebo RCT – no double standard Probiotic use would ideally be within a prospectively planned cohort study or RCT in a local or national or international network of NICUs

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Key points for parents “In randomized studies in over 2000 preterm babies, those given probiotics were half as likely to die or to get necrotizing enterocolitis (a severe gut disease).”

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Key points for parents “There was no increase in adverse effects, but these are still possible, particularly in the smallest infants.”

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Can we reach a consensus for global collaboration?

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Should placebo RCTs continue? YES –If clinicians are unconvinced by the evidence, or –If the only access to a previously evaluated probiotic product, shown to be effective in an earlier RCT, is through a placebo RCT and –If parents are fully informed and give consent

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Can a previously evaluated probiotic be made available by a special access scheme? YES - in certain jurisdictions, with Drug and Therapeutics Committee or IRB/ Executive approval A reputable supplier of a previously evaluated probiotic produced according to stringent guidelines for Good Manufacturing Practice Quality control by an accredited food standards laboratory with -random checks of each batch for extraneous pathogens -confirmation of colonisation in stools Detailed information to parents and their informed consent

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Options for clinicians and parents Those not convinced may wish to support ongoing placebo RCTs Those who are convinced may wish to use a previously evaluated probiotic (e.g. Bin Nun et al, 2005 or Lin et al, 2008) in previously published doses, after informed parental consent, and preferably in a prospectively planned cohort study within a local or national network or registry

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Sir Iain Chalmers Editor, James Lind Library Current attitudes to, and restrictions on, therapeutic research are powerful disincentives to people who wish to confront uncertainties about the effects of treatments. It is up to clinicians, patients, and the public in general to decide whether they wish to continue tolerating this bizarre state of affairs. Chalmers I. BMJ 2008; 337: a841

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Issue Response Comment Pooling RCTs of different probiotics is unacceptable ? Pooling is accepted in Cochrane Reviews of antibiotics, β blockers, tocolytics, surfactants, ventilation immunoglobulins and many others. Better estimates of short or long term risk ? Potential risks of probiotics must be balanced against the substantially increased risk of mortality in controls. Large cohort/ Phase IV studies may estimate risks more reliably than RCTs Rationale for further placebo RCTs

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Issue Response Comment Current meta analysis shows heterogeneity x There is no evidence of heterogeneity. Relative risks for mortality are < 1.0 and confidence intervals overlap. I 2 = 0. Access to probiotics may help clinicians gain experience √ But only half the infants get probiotics in RCTs. Special access schemes + cohort studies allow access for all infants. Clinicians remain substantially uncertain about the evidence √ Should clinicians discuss the options with parents and let them decide? Rationale for further placebo RCTs

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Ioannidis and Lau, PNAS 2001 Analysed cumulative meta analyses of 45 different treatments in perinatal medicine. Looked at how often there were big swings in the odds ratio for a treatment after a new trial was added to the analysis

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“With > 2000 patients... odds ratios (or Relative Risks) may still change by as much as to fold, but bigger swings have not been seen.”

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Current evidence of lower mortality is very unlikely to be nullified by more placebo RCTs.

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Cumulative meta-analyses of Magnesium Sulphate in Acute Myocardial Infarction and albumin in adult intensive care were shifted to the null by RCTs of 58,050 and 6,997. Neither was associated with a swing in odds ratio of > 2.0.